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PubMed This is a summary of 16 peer-reviewed journal articles Updated
Hematology

Decoding Your Labs: From "FS" to S-HPFH

At a Glance

An "FS" newborn screen can indicate severe sickle cell anemia or the benign condition S-HPFH. While waiting for definitive genetic testing to confirm S-HPFH, infants must immediately begin severe sickle cell protocols, including daily penicillin, to prevent life-threatening infections.

Receiving a sickle cell diagnosis—whether it is a newborn screening report for your child or a surprising lab result in adulthood—can be a confusing moment [1][2]. The labels used on these reports are often shorthand for complex biology, and understanding how to read between the lines is the first step toward clarity. For S-HPFH, the diagnostic journey often starts with a result that looks more concerning than it actually is.

The “FS” Result: A Critical Warning and a Common Starting Point

Most newborns are screened for sickle cell disease shortly after birth. If the screening report comes back with the letters “FS,” it means the lab detected two types of hemoglobin:

  • F (Fetal Hemoglobin)
  • S (Sickle Hemoglobin) [1].

Because “FS” is the exact same pattern seen in infants with HbSS (the most severe form of sickle cell anemia), many families are initially told their child has a serious disease [1][3]. At birth, every baby has high levels of Fetal Hemoglobin, so the screen cannot yet tell the difference between a baby who will lose that protection (HbSS) and a baby who will keep it forever (S-HPFH) [4][5].

CRITICAL MEDICAL PROTOCOL: Even if you suspect S-HPFH, any infant with an “FS” newborn screen MUST be treated as having severe HbSS until definitively proven otherwise. This includes starting life-saving preventative treatments like daily penicillin at two months of age. Without this medication, infants with HbSS are at an incredibly high risk for fatal pneumococcal sepsis. Never delay or refuse these treatments while waiting for an S-HPFH diagnosis [1][6].

Early Genetic Testing: The Definitive Answer

Historically, doctors had to wait six months or longer to see if a baby’s Fetal Hemoglobin levels dropped (indicating HbSS) or stayed high (indicating S-HPFH) [4]. Today, you do not have to wait. Modern clinical practice uses early definitive genetic testing to confirm the diagnosis rapidly [7][8]. By looking directly at the DNA, doctors can distinguish S-HPFH from severe sickle cell anemia without prolonging the anxiety.

Decoding the Advanced Labs

In older children and adults, doctors use detailed blood tests called HPLC or Hemoglobin Electrophoresis to evaluate S-HPFH.

  • HbA2 Levels: This is often the “smoking gun.” In S-HPFH, HbA2 levels are typically normal or low [9][10]. If the HbA2 is elevated (above 3.5%), it often points toward Sickle-Beta Thalassemia instead [9].
  • MCV (Mean Corpuscular Volume): This measures the size of the red blood cells. In S-HPFH, the cells are usually a normal size (normocytic). In thalassemia, the cells are often very small (microcytic) [11][12].
  • HbF Distribution: A specialized test (like flow cytometry) can confirm if the HbF is pancellular (found in every cell), which is a hallmark of S-HPFH [13].

Genetic “Blueprints”: MLPA and Sequencing

Doctors may use MLPA (Multiplex Ligation-dependent Probe Amplification), which is a high-tech way to look for “missing pieces” or deletions in the beta-globin gene cluster [7][14]. If a specific deletion is found, it provides a definitive diagnosis of deletional HPFH. In other cases, DNA sequencing is used to find tiny “typos” (point mutations) in the DNA that keep the HbF turned on [8][15].

Your Diagnostic Checklist

When you look at your lab report, ensure these pieces of data are present to get a complete picture:

  1. HbF Percentage: Is it consistently above 20%? [16]
  2. HbA2 Percentage: Is it in the normal range (ruling out Thalassemia)? [9]
  3. MCV: Are the red blood cells a normal size? [11]
  4. Genetic Confirmation: Has a DNA test rapidly confirmed the S-HPFH variant? [7]

Common questions in this guide

What does an FS result mean on a newborn sickle cell screen?
An "FS" result means the lab detected both fetal hemoglobin (F) and sickle hemoglobin (S). Because infants with severe sickle cell anemia also have this exact pattern at birth, babies are treated for severe disease until further genetic testing can definitively confirm if it is S-HPFH.
Why does my baby need penicillin if we suspect they have S-HPFH?
Even if you suspect benign S-HPFH, an infant with an "FS" screen must be treated as having severe sickle cell anemia until definitive genetic testing is complete. Daily penicillin is a critical, life-saving preventative treatment that protects against fatal pneumococcal sepsis.
How do doctors definitively confirm an S-HPFH diagnosis?
Modern clinical practice uses early definitive genetic testing, such as MLPA or DNA sequencing, to rapidly distinguish S-HPFH from severe sickle cell anemia. This looks directly at the DNA for specific deletions or mutations rather than waiting months to see if fetal hemoglobin levels drop.
What role do HbA2 levels play in diagnosing S-HPFH?
In S-HPFH, HbA2 levels are typically in the normal or low range. If the HbA2 levels are elevated above 3.5%, it usually points to a different condition called Sickle-Beta Thalassemia rather than S-HPFH.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Can we order immediate genetic testing to definitively diagnose S-HPFH without waiting months to see how HbF levels change?
  2. 2.Can you explain why the 'FS' result on the newborn screen requires starting penicillin immediately, even if we suspect S-HPFH?
  3. 3.Is the HbA2 level in the normal range, and how does that help confirm it's S-HPFH rather than Sickle-Beta Thalassemia?
  4. 4.If we haven't done it yet, can we use MLPA testing to see if there is a specific deletion in the beta-globin cluster?

Questions For You

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References

References (16)
  1. 1

    A Plea for the Newborn Diagnosis of Hb S-Hereditary Persistence of Fetal Hemoglobin.

    Serjeant GR, Serjeant BE, Hambleton IR, et al.

    Hemoglobin 2017; (41(3)):216-217 doi:10.1080/03630269.2017.1360336.

    PMID: 28870138
  2. 2

    Clinical Utility of the Addition of Molecular Genetic Testing to Newborn Screening for Sickle Cell Anemia.

    Shook LM, Haygood D, Quinn CT

    Frontiers in medicine 2021; (8()):734305 doi:10.3389/fmed.2021.734305.

    PMID: 34859003
  3. 3

    Blessing in disguise; a case of Hereditary Persistence of Fetal Hemoglobin.

    Shaukat I, Pudal A, Yassin S, et al.

    Journal of community hospital internal medicine perspectives 2018; (8(6)):380-381 doi:10.1080/20009666.2018.1536241.

    PMID: 30559951
  4. 4

    Phenotypic variation in sickle cell disease: the role of beta globin haplotype, alpha thalassemia, and fetal hemoglobin in HbSS.

    Serjeant GR

    Expert review of hematology 2022; (15(2)):107-116 doi:10.1080/17474086.2022.2040984.

    PMID: 35143361
  5. 5

    Sickle cell disease severity: an introduction.

    Pace BS, Goodman SR

    Experimental biology and medicine (Maywood, N.J.) 2016; (241(7)):677-8 doi:10.1177/1535370216641880.

    PMID: 27190296
  6. 6

    Retained Splenic Function in an Indian Population with Homozygous Sickle Cell Disease May Have Important Clinical Significance.

    Serjeant B, Hambleton I, Serjeant G

    Indian journal of community medicine : official publication of Indian Association of Preventive & Social Medicine 2021; (46(4)):715-718 doi:10.4103/ijcm.IJCM_1054_20.

    PMID: 35068741
  7. 7

    Detection of BRCA1/2 large genomic rearrangements in breast and ovarian cancer patients: an overview of the current methods.

    Concolino P, Capoluongo E

    Expert review of molecular diagnostics 2019; (19(9)):795-802 doi:10.1080/14737159.2019.1657011.

    PMID: 31429350
  8. 8

    A Comprehensive Strategy for Accurate Mutation Detection of the Highly Homologous PMS2.

    Li J, Dai H, Feng Y, et al.

    The Journal of molecular diagnostics : JMD 2015; (17(5)):545-53.

    PMID: 26320870
  9. 9

    Clinical variability and molecular characterization of Hbs/Gγ (Aγδβ)0-thal and Hbs/HPFH in Indian sickle cell disease patients: AIIMS experience.

    Pandey H, Singh K, Ranjan R, et al.

    Hematology (Amsterdam, Netherlands) 2019; (24(1)):349-352 doi:10.1080/16078454.2019.1579985.

    PMID: 30777489
  10. 10

    Genetic research and clinical analysis of deletional Chinese Gγ+(Aγδβ)0 -thalassemia and Southeast Asian HPFH in South China.

    Wu Y, Yao Q, Zhong M, et al.

    Annals of hematology 2020; (99(12)):2747-2753 doi:10.1007/s00277-020-04252-7.

    PMID: 32930850
  11. 11

    Sickle Cell Disease in Jordan: The Experience of a Major Referral Center.

    Oudat RI, Abualruz HS, Al-Shiek NKA, et al.

    Medical archives (Sarajevo, Bosnia and Herzegovina) 2021; (75(1)):27-30 doi:10.5455/medarh.2021.75.27-30.

    PMID: 34012195
  12. 12

    Cholelithiasis in patients with paediatric sickle cell anaemia in a Saudi hospital.

    Alhawsawi ZM, Alshenqeti AM, Alqarafi AM, et al.

    Journal of Taibah University Medical Sciences 2019; (14(2)):187-192 doi:10.1016/j.jtumed.2019.02.007.

    PMID: 31435409
  13. 13

    Heterogeneity of fetal hemoglobin production in adult red blood cells.

    Khandros E, Blobel GA

    Current opinion in hematology 2021; (28(3)):164-170 doi:10.1097/MOH.0000000000000640.

    PMID: 33631783
  14. 14

    Molecular Characterization of Three Novel Large Deletions Causing α0-Thalassemia.

    Ferrer-Benito S, Ricard Andrés MP, Murúzabal MJ, et al.

    International journal of molecular sciences 2025; (26(18)) doi:10.3390/ijms26188783.

    PMID: 41009357
  15. 15

    Mutation analyses by next-generation sequencing and multiplex ligation-dependent probe amplification in Japanese autosomal dominant polycystic kidney disease patients.

    Mochizuki T, Teraoka A, Akagawa H, et al.

    Clinical and experimental nephrology 2019; (23(8)):1022-1030 doi:10.1007/s10157-019-01736-3.

    PMID: 30989420
  16. 16

    The Natural History of Hb S/Hereditary Persistence of Fetal Hemoglobin in 13 Children from the State of Minas Gerais, Brazil.

    Belisário AR, Sales RR, Silva CM, et al.

    Hemoglobin 2016; (40(3)):215-9 doi:10.3109/03630269.2016.1149076.

    PMID: 27117574

This page explains S-HPFH lab results and newborn screening for educational purposes only. Always consult your hematologist or pediatrician to interpret your specific genetic and blood tests.

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